The human gamma-herpesviruses, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus evade host immunity and establish life-long, latent infections. Latent infections are associated with the development of a variety of malignancies, particularly in immunocompromised AIDS patients. There are currently no effective vaccines for this important class of human viruses. We propose to exploit the in vivo mouse gamma- herpesvirus model to test efficacy of genetically engineered viruses as vaccines. We have shown that a latency-deficient virus fails to establish latency in 100% of recipients, and there is no in vivo reversion to wild type virus, thus fulfilling safety criteria for a genetically engineered oncogenic virus. Importantly, the vaccinated mice are protected from both latent and lytic infection following a subsequent challenge with wild type virus, thus showing protective efficacy. In the current proposal, we will further exploit the natural mouse gamma- herpesvirus infection model to test the parameters and immune correlates of protection of the latency-deficient vaccine. In addition, we will explore the vaccination efficacy of a second genetically engineered virus, which is replication-deficient. Finally, we will evaluate the impact of a further deletion of two immune evasion genes on efficacy and immune correlates of protection. Elucidation of mechanisms of protective immunity induced by "proof of concept" vaccination strategies in the experimental mouse model will provide fundamental basic insight necessary for the development of vaccines for the oncogenic human gamma-herpesviruses. PUBLIC HEALTH RELEVANCE: The gamma-herpesviruses are not cleared by the host immune system, but establish persistent latent infections. They are widely disseminated in the human population and are associated with the development of several types of cancer, especially in immunocompromised AIDS patients. An important clinical goal is to develop vaccines to prevent infection. Study of the experimental mouse model will enhance our understanding of the immune mechanisms involved in controlling infection and reveal fundamental principles that can be applied to human vaccine development. As there are currently no effective vaccines for the gamma- herpesviruses, these studies are highly significant for human health.